The goal of this grant is to investigate brain alpha7 nicotinic receptors and their potential as targets for developing drugs for Alzheimer's disease. These receptors have been found to be neuroprotective under a variety of conditions as well as able to improve memory related behaviors in every species evaluated. Recent results also indicate functional interactions between these receptors and amyloid precursor protein (APP) derived peptides. We propose to evaluate these actions of alpha7 nicotinic receptors using GTS-21 and related compounds, which are selective agonists for the receptors. Studies will focus on 3 models: 1) mice that have undergone fimbria-fomix axotomy of the septohippocampal pathway; 2) double transgenic APP/PS1 mice that overexpress Swedish mutant APP695 and mutant presenilin 1 (PS1); and 3) cell cultures expressing alpha7 nicotinic receptors. Aim 1 determines if activation of intracellular or voltage sensitive calcium channels is necessary for the neuroprotective action of alpha7 nicotinic receptor agonists. Aim 2 determines whether GTS-21 and a more efficacious alpha7 receptor agonist we developed protect both septal cholinergic and non-cholinergic neurons from axotomy in amyloid-overexpressing APP/PS1 double transgenic mice. Aim 3 evaluates the effects of GTS-21 on amyloid deposition in the APP/PS1 mouse, based on the observation that chronic nicotine treatment reduces these deposits by 80%. It also evaluates the effects of this drug on memory related deficits in these animals following chronic treatment.